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Endocrinology Vol. 145, No. 3 1203-1210
Copyright © 2004 by The Endocrine Society

Distribution of the VPAC2 Receptor in Peripheral Tissues of the Mouse

Anthony J. Harmar, W. John Sheward, Christine F. Morrison, Beatrice Waser, Mathias Gugger and Jean Claude Reubi

Division of Neuroscience (A.J.H., W.J.S., C.F.M.), School of Biomedical and Clinical Laboratory Sciences, University of Edinburgh, Edinburgh, United Kingdom EH8 9JZ; and Institute of Pathology (B.W., M.G., J.C.R.), University of Berne, CH-3010 Berne, Switzerland

Address all correspondence and requests for reprints to: Prof. Anthony J. Harmar, Division of Neuroscience, School of Biomedical and Clinical Laboratory Sciences, University of Edinburgh, 1 George Square, Edinburgh, United Kingdom EH8 9JZ. E-mail: tony.harmar{at}ed.ac.uk.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
The neuropeptide vasoactive intestinal peptide (VIP) exerts its actions through two structurally related G protein-coupled receptors (VPAC1 and VPAC2). Pituitary adenylate cyclase-activating polypeptide (PACAP) is also a potent agonist of VPAC1 and VPAC2 receptors as well as of a third, PACAP-specific receptor (PAC1). We report here the distribution of the VPAC2 receptor in peripheral tissues of the mouse, determined by receptor autoradiography using [125I]VIP and the selective VPAC2 receptor agonist [125I]Ro25-1553 in wild-type and VPAC2 receptor-null mice. In addition, displacement experiments with the VPAC2-selective agonist Ro25-1553 and the VPAC1-selective agonist [K15,R16,L27]VIP(1–7)/GRF(8–27) were performed using the universal radioligand [125I]VIP. The VPAC2 receptor is found predominantly in smooth muscle (in blood vessels and in the smooth muscle layers of the gastrointestinal and reproductive systems), the basal part of the mucosal epithelium in the colon, lung, the vasculature of the kidney, adrenal medulla, and retina. Unexpectedly, the receptor was also present in thyroid follicular cells and acinar cells of the pancreas, tissues that have not been found to express the receptor in other species, and in very large amounts in the lung. Our data suggest novel functions of the VPAC2 receptor and additional potential therapeutic uses of drugs acting at the receptor (including the treatment of erectile dysfunction), but our results also indicate that caution should be exercised in using the mouse as an animal model for the evaluation of VIP analogs intended for diagnostic or therapeutic use in man.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
THE VPAC2 RECEPTOR was first cloned from the rat olfactory bulb (1) and cDNAs encoding the receptor have subsequently been sequenced from human (2) and mouse (3). In the central nervous system, the VPAC2 receptor is most abundant in the suprachiasmatic nuclei, where it plays a role in the control of the circadian clock (4, 5) and in the thalamus, hypothalamus, midbrain, and brainstem (6, 7, 8). In situ hybridization histochemistry has been used to demonstrate expression of the VPAC2 receptor in a number of peripheral organs of the rat (8), most abundantly in lung and gastrointestinal tract. In man, receptor autoradiography has shown that the VPAC2 receptor is present in smooth muscles from a variety of peripheral organs, including the gastrointestinal tract, the urogenital tract, and the vascular system (9). However, to date there has been no systematic study of the distribution of the receptor in peripheral tissues in any species. In this study we have defined the distribution of the VPAC2 receptor in 31 peripheral tissues in the mouse. Two related methods that have been used to identify VPAC2 receptors in tissue sections were used in this study: receptor autoradiography with the VPAC2 receptor-selective agonist [125I]Ro25-1553, first used by Vertongen et al. (7) to map the distribution of the VPAC2 receptor in the rat brain, and assessment of [125I]VIP binding in the presence or absence of Ro25-1553 (10) or of the VPAC1-selective agonist [K15,R16,L27]VIP(1–7)/GRF(8–27) (KRL) (11, 12). Studies of [125I]Ro25-1553 and [125I]VIP binding in VPAC2 receptor-null mice (4) were used to confirm our conclusions and to assist in the interpretation of autoradiographic data.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Experimental animals
All animal procedures were carried out in compliance with United Kingdom Home Office animal welfare regulations. Adult male and female wild-type C57BL/6 and VPAC2 receptor-null (Vipr2-/-) mice were killed by cervical dislocation. Samples of all major peripheral organs and tissues were rapidly dissected (Table 1GoGo). The stomach and gastrointestinal tract were removed in their entirety and the contents were removed by flushing through with ice-cold sterile PBS before tissue collection. All tissue samples were immediately frozen on dry ice and stored at -80 C until required for analysis.


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  		TABLE 1. Distribution of VPAC2 receptors in peripheral tissues of the mouse, determined by radioligand binding

 

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  		TABLE 1A. Continued

 
Receptor autoradiography
Receptor autoradiography was performed on 10- and 20-µm-thick cryostat sections of the tissue samples, as described previously (10), using [125I]VIP and [125I]Ro25-1553 as radioligands. In any given tissue, the presence in wild-type mice, but not in Vipr2-/- mice, of binding sites for [125I]Ro 25-1553 and for [125I]VIP that could be displaced by [125I]Ro 25-1553 (20 nM), but not by the VPAC1-selective ligand KRL (20 nM), was taken as conclusive evidence of the expression of VPAC2 receptors. Although the distribution of VPAC1 receptors was not examined systematically in this study, tissues expressing VPAC1 receptors were identified as those possessing binding sites for [125I]VIP, which were present in both wild-type and in Vipr2-/- mice and could be displaced by KRL (20 nM), but not by Ro 25-1553 (20 nM).


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
The abundance of the VPAC2 receptor in peripheral tissues was determined by specific binding of the selective VPAC2 receptor agonist, [125I]Ro25-1553. Confirmation of the identity of binding sites was obtained by 1) binding of [125I]VIP in the presence of an excess of Ro25-1553 (to identify VPAC1 receptor binding sites), 2) binding of [125I]VIP in the presence of an excess of KRL (to identify VPAC2 receptor binding sites), and 3) comparison of binding of [125I]Ro25-1553 between wild-type and Vipr2-/- mice (in which VPAC2 receptor-binding sites are absent). In almost all tissues, it was possible to identify and quantify VPAC2 receptor-binding sites unequivocally using these techniques. In the liver, there was modest binding of [125I]Ro25-1553 that was also present in VPAC2 knockout animals; we interpret this as low affinity binding to the very high number of VPAC1 sites expressed in this tissue. Table 1GoGo summarizes all of the data.

Digestive system
VPAC2 receptors were present in smooth muscle, and VPAC1 receptors were present in mucosa throughout the gastrointestinal tract (Table 1GoGo). VPAC2 receptors were also present in the muscularis mucosa of the stomach; the resolution of the autoradiographic technique did not permit us to determine whether VPAC2 receptors were also present in muscularis mucosa in other parts of the gastrointestinal tract. In the colon, VPAC2 receptors were expressed at high levels in the basal part of the mucosal epithelium. In the liver, there was strong expression of the VPAC1 receptor, as determined by binding of [125I]VIP that was displaced by KRL; although there was modest binding of [125I]Ro25-1553 in the liver, this binding was also present in VPAC2 knockout animals, and we interpret this as low affinity binding to the very high number of VPAC1 sites expressed in this tissue. VPAC2 receptors were expressed at very high levels in pancreatic acinar cells, with pancreatic islets appearing as regions of much lower [125I]Ro25-1553 binding. However, because of the resolution of the autoradiographic technique and the very high expression in acinar cells, we could not exclude the possibility that there are functionally significant levels of VPAC2 receptors in pancreatic islets and/or in pancreatic ducts. VPAC2 receptors were not detected in the gall bladder.

Endocrine organs
VPAC2 receptors were abundant in follicular cells of the thyroid (see Fig. 1Go). There was significant expression of VPAC2 in the adrenal medulla as well as in the adrenal capsule (Table 1GoGo). It should be noted, however, that the main VIP/PACAP receptor expressed in the mouse adrenal is the PAC1 receptor (Reubi, J. C., unpublished data).



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  		FIG. 1. Autoradiography of VIP receptors in the thyroid gland of wild-type mice using [125I]Ro25-1553 (A–C) and [125I]VIP (D–G) as radioligands. A, Hematoxylin-eosin stained section. Bar, 1 mm. T, Trachea; Th, thyroid. B, Total binding of [125I]Ro25-1553 showing labeling of the thyroid gland. C, Nonspecific binding in the presence of 10-7 M Ro25-1553. The binding in the thyroid represents specific binding, whereas the other tissues have nonspecific binding only. D, Total binding of [125I]VIP. E, Binding of [125I]VIP in the presence of 20 nM VIP. F, Binding of [125I]VIP in the presence of 20 nM KRL. G, Binding of [125I]VIP in the presence of 20 nM Ro25-1553. Displacement of [125I]VIP binding is seen with VIP and Ro25-1553, but not with KRL, indicating the presence of VPAC2 receptors.

 
Urogenital system
In the female genital tract, VPAC2 receptors were present in the smooth muscle of the fallopian tube, oviduct, and uterus, whereas VPAC1 receptors were seen in the uterine glands (Fig. 2Go). In male mice, VPAC2 receptors were present in the smooth muscle of the epididymis and vas deferens, but were not expressed at high levels in prostate, where the predominant VIP receptor was the VPAC1 subtype, expressed in epithelial cells. VPAC2 receptors were very abundant in the corpora cavernosa of the penis, whereas VPAC1 receptors were seen in the urethral epithelium. There was abundant specific binding of [125I]Ro25-1553 to the tunica albuginea of the testis, but VPAC2 receptors were not detected elsewhere in the testis or in spermatozoa. In contrast, VPAC1 receptors were expressed in Leydig cells of the testis. VPAC2 receptors were not detected in the bladder or kidney (except in blood vessels in the renal cortex: see Fig. 3Go).



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  		FIG. 2. VIP receptors in the mouse uterus. A, D, and I, Hematoxylin-eosin stained sections. m, Muscle; gl, glands. Bars, 1 mm. B, Total binding of [125I]Ro25-1553 in a wild-type mouse, showing labeling of the muscle. C, Nonspecific binding of [125I]Ro25-1553 in the presence of 10-7 M Ro25-1553. E–H and J–M, [125I]VIP binding in wild-type (E–H) or VPAC2 receptor-null (J–M) mice. E and J, Total binding of [125I]VIP. F and K, Binding of [125I]VIP in the presence of 20 nM VIP. G and L, Binding of [125I]VIP in the presence of 20 nM KRL. H and M, Binding of [125I]VIP in the presence of 20 nM Ro25-1553. Glands and muscles are labeled in the wild-type mouse (E), whereas only glands are labeled in the VPAC2 receptor-null mouse (J). Labeling of the glands was displaced by KRL, whereas labeling of the muscle was displaced by Ro25-1553.

 


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  		FIG. 3. VPAC2 receptors in the wild-type mouse kidney. A, Hematoxylin-eosin-stained section. Bar, 1 mm. B, Total binding of [125I]Ro25-1553. Cortical vessels are labeled. C, Nonspecific binding (in the presence of 10-7 M Ro25-1553).

 
Lymphatic system
Very little specific binding of [125I]Ro25-1553 was seen in the spleen or lymph nodes of the mouse. The predominant VIP receptor in these tissues was the VPAC1 receptor, present in the white pulp of the spleen and in lymphocytes in lymph nodes. In the thymus, the predominant VIP receptor was also the VPAC1 subtype, expressed in the medulla (Table 1GoGo).

Other tissues
VPAC2 receptors were present in blood vessels in many tissues of the mouse, e.g. renal cortex (Fig. 3Go) and skeletal muscle. The VPAC2 receptor was not detected in the heart. VPAC2 receptors were present in large amounts in the alveoli of the lung. The low resolution of the autoradiographic technique, however, did not allow us to determine whether they were expressed by the lung endothelium, epithelium, or both. However, as the VPAC2 receptor was not detected in endothelium in other tissues, we consider it likely that the receptor is present in epithelial cells. Conversely, VPAC1 receptors were present in cells of the tracheal and bronchial epithelia (see Fig. 4Go). VPAC2 receptors were not detected in skeletal muscle (except in blood vessels; see above) or in adipose tissue. A very high density of VPAC2 receptors was observed in the mouse retina (Fig. 5Go).



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  		FIG. 4. VPAC2 receptors in the lung. Binding of [125I]Ro25-1553 in wild-type (A–C) and VPAC2 receptor-null (D–F) mice. A and D, Hematoxylin-eosin-stained sections. Bars, 1 mm. B and E, Total binding of [125I]Ro25-1553. Strong labeling is seen in the lungs of wild-type mice (B) only. C and F, Nonspecific binding (in the presence of 10-7 M Ro25-1553). G–J, [125I]VIP binding in wild-type mice. G, Total binding of [125I]VIP. I, Binding of [125I]VIP in the presence of 20 nM VIP. H, Binding of [125I]VIP in presence of 20 nM KRL. J, Binding of [125I]VIP in the presence of 20 nM Ro25-1553. [125I]VIP binding is displaced by VIP or Ro25-1553 in the alveoli (a) and by VIP or KRL in the bronchial epithelium (b). Alveoli have VPAC2 receptors, and the bronchial epithelium has VPAC1 receptors.

 


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  		FIG. 5. VPAC2 receptors in the retina. [125I]Ro25-1553 binding in wild-type (A–C) and VPAC2 receptor-null (D–F) mice. A and D, Hematoxylin-eosin-stained sections. r, Retina. Bars, 1 mm. B and E, Total binding of [125I]Ro25-1553. Strong labeling is seen in the retina of the wild-type animal. C and F, Nonspecific binding (in the presence of 10-7 M Ro25-1553). G–J, [125I]VIP binding in wild-type mice. G, Total binding of [125I]VIP. I, Binding of [125I]VIP in the presence of 20 nM VIP. H, Binding of [125I]VIP in the presence of 20 nM KRL. J, Binding of [125I]VIP in the presence of 20 nM Ro25-1553. [125I]VIP binding is displaced by VIP and Ro25-1553, indicative of the presence of VPAC2 receptors.

 
Table 1GoGo indicates the organs that have a different distribution of VPAC2 receptor in the mouse and human. Significant differences are seen in thyroid, lung, pancreas, and colon.


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Our results extend and confirm previous studies in man and other species that suggest that the VPAC2 receptor is found predominantly in smooth muscle of blood vessels and in the smooth muscle layers of other organs, but provide a more comprehensive picture of the distribution of this receptor than has been available previously. The receptor is present in smooth muscle layers at all levels of the gastrointestinal tract from esophagus to rectum; in the fallopian tube, oviduct, and uterus; in the epididymis and vas deferens; and in blood vessels in many tissues.

The two endogenous ligands of the VPAC2 receptor, VIP and PACAP, are extensively colocalized in the peripheral nervous system (13). However, because there is more comprehensive information on the distribution of VIP in peripheral tissues, our consideration of possible physiological functions of the VPAC2 receptor is focused on possible actions of VIP. In the future, physiological studies of VIP-null (14) and PACAP-null (15) mice may make it possible to determine which of the two endogenous ligands is physiologically significant in each of the tissues where the receptor is expressed.

VPAC2 receptors were present in smooth muscles of the male and female reproductive tracts (uterus, fallopian tube, oviduct, epididymis, and vas deferens), where the receptor is likely to transduce the effects of VIP released from postganglionic cholinergic neurons of the parasympathetic nervous system (16). Expression of the VPAC2 receptor has also been demonstrated in uterine smooth muscle in the rat (8) and human (10). The VPAC2 receptor was also present in abundance in the corpora cavernosa of the penis. It is well established that erectile tissue in both rodents (17) and man (18) is heavily innervated with cholinergic neurons containing VIP. Intracavernosal injection of VIP in combination with the adrenergic drug phentolamine mesylate has been shown to be an effective treatment of human erectile dysfunction (19), and transdermal application of (nonselective) lipophilic VIP derivatives has been shown to be an effective treatment in rodent models of impotence (20). Our findings suggest that the VPAC2 receptor is responsible for mediating these effects of VIP and indicate that selective VPAC2 agonists may be useful as new treatments for this disorder.

In the gastrointestinal tract, VIP is present in intrinsic neurons of the mesenteric plexus, where it is thought to function as a major transmitter mediating smooth muscle relaxation and has been implicated in the descending relaxation component of the peristaltic reflex (21). Consistent with studies in man (9, 10) and rat (8), VPAC2 receptors were present in smooth muscle throughout the gastrointestinal tract. Our results suggest that the VPAC2 receptor may mediate many of the relaxant effects of VIP on the gastrointestinal tract, consistent with the findings of Robberecht et al. (22), who identified the VPAC2 receptor as the predominant receptor subtype mediating the relaxant effect of VIP in the rat gastric fundus. VIP is also abundant in neurons of the submucous plexuses of the gastrointestinal tract (23, 24), where it is substantially colocalized with nitric oxide synthase (24). VPAC2 receptors were present at high levels in the basal mucosa of the colon and may thus mediate the effects of VIP on electrolyte secretion in the colon, but not elsewhere in the gut. The role of VPAC2 receptors in the muscularis mucosae of the stomach, also reported in the rat (8), remains unknown.

Consistent with studies in man (9, 10), blood vessels in many tissues of the mouse, e.g. renal cortex and skeletal muscle, expressed VPAC2 receptors. The VPAC2 receptor is thus a strong candidate for the receptor mediating the profound vasodilator effects of VIP that first led to the identification and isolation of this peptide (25). However, expression of the VPAC1 receptor has also been demonstrated in certain blood vessels in man (9, 10, 26) and in rodents (27).

An extremely high density of VPAC2 receptors was found in the retina, consistent with previous studies demonstrating the expression of this receptor in the rat (28) and fetal human retina (29). VIP has been reported to exert neuroprotective actions (30), to facilitate glutamate-evoked acetylcholine release (31), and to modulate {gamma}-aminobutyric acidA receptor function in bipolar cells and ganglion cells of the rodent retina (32). However, it is not clear whether any of these responses is mediated through VPAC2 receptors.

Species differences in the expression of VPAC2 receptors
We observed a number of apparent differences between the distribution of the VPAC2 receptor in the mouse and that reported in other species (8, 9, 10, 33, 34, 35). Some of these studies reported the localization of VPAC2 receptor mRNA, which may not be translated into protein with equal efficiency in all tissues. Nevertheless, comparison of our findings with other studies at the protein level suggests that there are a number of significant differences in the distribution of the VPAC2 receptor between species.

Wei and Mojsov (33) used Northern blot analysis of RNA from human tissues to define the distribution of the VPAC2 receptor in man. Some tissues identified as expressing the VPAC2 receptor in that study (skeletal muscle, kidney, and adipose tissue) were not found to express the VPAC2 receptor in the mouse. It is possible that there are differences between species in the expression of the VPAC2 receptor in these tissues, but it is more likely that the RNA detected by Wei and Mojsov (33) originated in the blood vessels present in these tissues.

Very little specific binding of Ro25-1553 was seen in the spleen, thymus, or lymph nodes of the mouse. The predominant VIP receptor in these tissues was the VPAC1 receptor, present in the white pulp of the spleen, in lymphocytes in lymph nodes, and in the medulla of the thymus. These data are consistent with studies indicating that the VPAC1 receptor is expressed constitutively in mouse T cells, whereas the VPAC2 receptor is induced by immune stimuli (36). However, in situ hybridization studies of the rat, indicating the presence of VPAC2 receptors in the white pulp and in some reticular cells within the red pulp of the spleen (8), suggest that there may be differences between rodent species in the role of VPAC2 receptors in the immune system.

In the mouse testis, VPAC2 receptors were only observed in the tunica albuginea, whereas in the rat, VPAC2 receptor mRNA has been detected by RT-PCR and in situ hybridization in germ cells, seminiferous tubules, and spermatozoa (8, 34). There may be a species difference between rats and mice in the expression of VPAC2 receptors in the testis, but it is also possible that VPAC2 receptor mRNA is not translated into protein in this tissue.

Whereas the VPAC1 receptor is the predominant type of VIP receptor expressed in the human thyroid (9), we found that VPAC2 receptors were abundant in follicular cells of the mouse thyroid, consistent with reports that VIP and helodermin (a VIP-like peptide with some selectivity for the VPAC2 receptor subtype) (37) stimulate thyroid hormone secretion in rodents (38).

In the mouse, we found very high expression of the VPAC2 receptor in acinar cells of the pancreas, consistent with an earlier study using mice containing a human VPAC2 receptor transgene (39). In the human pancreas, the VPAC2 receptor was not detected, and VPAC1 receptors were expressed predominantly in pancreatic ducts (10), whereas in the rat, VPAC1 and VPAC2 receptors were expressed at comparable levels in pancreatic acini (35), and the VPAC2 receptor was expressed at higher levels in islets than in acinar tissue (8).

The lungs and kidneys are further examples for the species selectivity of VIP receptor expression. Whereas the mouse lung expresses high amounts of VPAC2 receptors, presumably located in the epithelium, the human lung expresses predominantly VPAC1 receptors (9, 10, 40), although VPAC2 mRNA was also identified in lung epithelium in one study (41). Interestingly, however, the epithelia of larger bronchi in the mouse express predominantly VPAC1 receptors. Although mouse and human kidneys express VPAC2 receptors in blood vessels, the human kidney has abundant VPAC1 receptors in glomeruli (9) that are not identified in the mouse in this location.

Our results indicate that because of significant species differences in receptor distribution, the mouse may not be an appropriate animal model for the development of VIP analogs intended for therapeutic use in man or for the diagnosis of human tumors (42, 43) by radioscintigraphy. Particular caution will be necessary when analyzing such animal data. For instance, if a novel VIP ligand with VPAC1 selectivity is evaluated in a mouse model for its biodistribution, its low lung uptake will be considered a positive characteristic, although the same radioligand tested in humans will, unfortunately, label the VPAC1 receptor-expressing lungs.

Our results suggest that the VPAC2 receptor may play a widespread role in the control of smooth muscle tone in the cardiovascular, gastrointestinal, and reproductive systems and may also have physiological functions in the adrenal medulla, thyroid gland, and exocrine pancreas. Studies of VPAC2 receptor-null mice should permit the elucidation of these potential physiological and endocrine roles and the identification of new potential targets for VPAC2 receptor ligands in the treatment of disease.


   Acknowledgments
 
We thank Dr. Patrick Robberecht for providing the VPAC1- and VPAC2-selective ligands KRL and Ro25-1553.


   Footnotes
 
This work was supported by the United Kingdom Medical Research Council.

Abbreviations: GRF, GH-releasing factor; KRL, [K15,R16,L27]VIP(1–7)/GRF(8–27); PACAP, pituitary adenylate cyclase-activating polypeptide; VIP, vasoactive intestinal peptide.

Received August 15, 2003.

Accepted for publication November 6, 2003.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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